HIV Genetic Variability

Principal Investigator:

Human immunodeficiency virus (HIV) mutates at high rates due to the absence of effective proof-reading activity associated with viral reverse transcriptase. It has long been known that virus mutant swarms (mutant distributions termed quasispecies) contain useful variants. Selection of virus variants represents an important mechanism for immune evasion, virus persistence and resistance to antiviral agents. Mutant spectra are the target on which selection and random drift act to shape the long-term evolution of viruses. Although the patterns and levels of HIV genetic variation have been well characterized in the last two decades, much remains to be discovered. To this end, we are studying HIV quasispecies in vivo at high resolution in order to determine the relationships between viral genotype, phenotype and fitness. Because specific processing of viral polypeptides is a critical stage in the replication and maturation of infectious particles as well as an important target in viral therapeutics, the HIV protease has been a model system in our group during the last 10 years. We are also estimating the distribution of fitness effects caused by random mutations (generated in vitro) on protease function. The evolution of natural proteins is thought to have occurred by successive fixation of individual mutations, it may be relevant to explore protein tolerance to substitutions to understand the evolution of natural proteins. Recently, we have extended these studies to the hepatitis C virus (HCV) NS3/4 protease. The HCV, a positive-stranded RNA virus, is the causal agent of a chronic liver infection afflicting 50% of the HIV infected-individuals from our Clinical Unit.

After the demonstration in 2001 that the gene-silencing mechanism mediated by RNA interference (RNAi) was conserved in mammalian cells, we decided to explore whether RNAis were able to specifically inhibit HIV replication. Indeed, we and others have shown that RNAi may provide an important new therapeutic approach for treating HIV infection. We are exploring how the virus could escape the inhibition by RNAis as well as designing strategies to reduce the emergence of viruses escaping from RNA interference-mediated inhibition.

A better understanding of the evolutionary potential of HIV and HCV will improve the development of better antiviral drugs and vaccines as well as better clinical management of HIV infected patients.

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